Serotonin (5-hydroxytryptamine) (5-HT) receptors play a critical role in many physiological and behavioral functions in humans and animals. These functions are mediated through various 5-HT receptors distributed throughout the body. There are now approximately fifteen different human 5-HT receptor subtypes that have been cloned, many with well-defined roles in humans. One of the most recently identified 5-HT receptor subtypes is the 5-HT6 receptor, first cloned from rat tissue in 1993 (Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. Molecular Pharmacology 1993, 43, 320-327, incorporated herein by reference in its entirety) and subsequently from human tissue (Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D. R. Journal of Neurochemistry 1996, 66, 47-56, both of which are incorporated herein by reference in their entireties). The receptor is a G-protein coupled receptor (GPCR) positively coupled to adenylate cyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.; Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical Research Communications 1993, 193, 268-276, incorporated herein by reference in its entirety) The receptor is found almost exclusively in the central nervous system (CNS) areas both in rat and in human. In situ hybridization studies of the 5-HT6 receptor in rat brain using mRNA indicate principal localization in the areas of 5-HT projection including striatum, nucleus accumbens, olfactory tubercle, and hippocampal formation (Ward, R. P.; Hamblin, M. W.; Lachowicz, J. E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64, 1105-1111, incorporated herein by reference in its entirety).
There are many potential therapeutic uses for 5-HT6 ligands in humans based on direct effects and on indications from available scientific studies. These studies include the localization of the receptor, the affinity of ligands with known in vivo activity, and various animal studies conducted so far.
One potential therapeutic use of modulators of 5-HT6 receptor function is in the enhancement of cognition and memory in human diseases such as Alzheimer's disease. The high levels of receptor found in important structures in the forebrain, including the caudate/putamen, hippocampus, nucleus accumbens, and cortex suggest a role for the receptor in memory and cognition since these areas are known to play a vital role in memory (Gerard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M. C.; Verge, D.; Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research, 1997, 746, 207-219, incorporated herein by reference in its entirety). The ability of known 5-HT6 receptor ligands to enhance cholinergic transmission also supported the potential cognition use (Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden, C. A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999, 126(7), 1537-1542, incorporated herein by reference in its entirety). Studies have found that a known 5-HT6 selective antagonist significantly increased glutamate and aspartate levels in the frontal cortex without elevating levels of noradrenaline, dopamine, or 5-HT. This selective elevation of neurochemicals known to be involved in memory and cognition strongly suggests a role for 5-HT6 ligands in cognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal of Pharmacology, 2000, 130(1), 23-26, incorporated herein by reference in its entirety). Animal studies of memory and learning with a known selective 5-HT6 antagonist found some positive effects (Rogers, D. C.; Hatcher, P. D.; Hagan, J. J. Society of Neuroscience, Abstracts 2000, 26, 680, incorporated herein by reference in its entirety). Further support for the role of a selective 5-HT6 ligand in cognition can be found in Woolley, M. L.; Marsden, C. A.; Sleight, A. J.; and Fone, K. C. F., Psychopharmacology, 2003, 170(4), 358-367, incorporated herein by reference in its entirety.
A related potential therapeutic use for 5-HT6 ligands is the treatment of attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in both children and adults. Because 5-HT6 antagonists appear to enhance the activity of the nigrostriatal dopamine pathway and because ADHD has been linked to abnormalities in the caudate (Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.; Cohen, R. M. Journal of Neuroscience 1998, 18(15), 5901-5907, incorporated herein by reference in its entirety), 5-HT6 antagonists may attenuate attention deficit disorders.
Early studies examining the affinity of various CNS ligands with known therapeutic utility or a strong structural resemblance to known drugs suggests a role for 5-HT6 ligands in the treatment of schizophrenia and depression. For example, clozapine (an effective clinical antipsychotic) has high affinity for the 5-HT6 receptor subtype. Also, several clinical antidepressants have high affinity for the receptor as well and act as antagonists at this site (Branchek, T. A.; Blackburn, T. P. Annual Reviews in Pharmacology and Toxicology 2000, 40, 319-334, incorporated herein by reference in its entirety).
Further, recent in vivo studies in rats indicate 5-HT6 modulators may be useful in the treatment of movement disorders including epilepsy (Stean, T.; Routledge, C.; Upton, N. British Journal of Pharmacology 1999, 127 Proc. Supplement 131P and Routledge, C.; Bromidge, S. M.; Moss, S. F.; Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.; Upton, N.; Clarke, S. E.; Brown, A. M. British Journal of Pharmacology 2000, 130(7), 1606-1612, each of which is incorporated herein by reference in its entirety).
Taken together, the above studies strongly suggest that compounds which are 5-HT6 receptor modulators, i.e. ligands, may be useful for therapeutic indications including: the treatment of diseases associated with a deficit in memory, cognition, and learning such as Alzheimer's and attention deficit disorder; the treatment of personality disorders such as schizophrenia; the treatment of behavioral disorders, e.g., anxiety, depression and obsessive compulsive disorders; the treatment of motion or motor disorders such as Parkinson's disease and epilepsy; the treatment of diseases associated with neurodegeneration such as stroke and head trauma; or withdrawal from drug addiction including addiction to nicotine, alcohol, and other substances of abuse.
Another of the 5-hydroxytryptamine receptors, the 5-HT2A receptor, has also been found to be important in a number of areas, including the regulation of the cardiovascular and central nervous systems, and the control of body temperature and vasomotor symptoms. Consistent with this receptor's involvement with regulation of the central nervous system, modulators of the 5-HT2A receptor may be beneficial in the treatment of neurological conditions such as schizophrenia, tardive dyskinesia, depression, suicidality, anxiety, panic disorder, obsessive-compulsive disorder, sleep disorders such as insomnia, eating disorders such as anorexia nervosa and dependency or acute toxicity associated with certain psychotomimetic agents such as LSD or MDMA (de Angelis, L. Current Opinion in Investigational Drugs 2002, 3(1), 106; Meltzer, H. Y. Neuropsychopharmacolgy 1999, 21, 106S; Leysen, D.; Linders, J. T. M.; Ottenheijm, H. C. J. Current Pharmaceutical Design 1997, 3, 367, each of which is incorporated herein by reference in its entirety). Additionally, recent in vivo studies also have suggested the use of 5-HT2A modulators for treating inflammatory or neuropathic pain (Nishiyama T. European Journal of Pharmacology 2005, 516, 18; Nitanda, A.; Yasunami, N.; Tokumo, K.; Fujii, H.; Hirai, T.; Nishio, H. Neurochemistry International 2005, 47(6), 394, each of which is incorporated herein by reference in its entirety).
In addition to its importance to the nervous system, the 5-HT2A receptor is also found in the cardiovascular system. Hence, compounds with 5-HT2A modulatory activity have benefit for the prophylaxis or treatment of cardiovascular conditions including coronary artery disease, myocardial infarction, transient ischemic attack, angina, atrial fibrillation, reducing platelet aggregation and reducing the risk of blood clot formation. (Doggrell, S. A. Expert Opinion on Investigational Drugs 2003, 12(5), 805, incorporated herein by reference in its entirety).
Additionally, recent reports have identified a function for the 5-HT2A receptor in temperature regulation (Mazzola-Pomietto, P.; Aulakh, C. S.; Wozniak, K. M.; Hill J. L.; Murphy, D. L. Psychopharmacolgy 1995, 117, 193, incorporated herein by reference in its entirety). Accordingly, 5-HT2A receptor antagonists have been effective in preventing the development of hyperthermia in animal models of serotonin syndrome (Nisijima, K.; Yoshino, T.; Yui, K.; Katoh, S. Brain Research 2001, 890, 23, incorporated herein by reference in its entirety).
Further, it has been hypothesized that the 5-HT2A receptor plays a key role in the occurrence of hot flushes and night sweats following menopause (Berendsen H. H. G., Maturitas, 2000, 36, 155, incorporated herein by reference in its entirety). Studies have shown that a low blood estrogen level correlates with a high concentration of the 5-HT2A receptor subtype on blood platelets (Biegon, A. Effects of steroid hormones on the serotonergic system. In: Whitaker-Azmitia, P. M.; Peroutka S. J. editors. The Neuropharmacology of Serotonin. 1990, 427-34, incorporated herein by reference in its entirety) and an upregulation of central 5-HT2A receptors (Fink G.; Sumner B. E. H. Nature, 1996, 383, 306, incorporated herein by reference in its entirety). The 5-HT2A and 5-HT2C receptor antagonist, mirtazapine, was effective in reducing the frequency and intensity of hot flushes (Waldinger M. D.; Berendsen, H. H. G.; Schweitzer, D. H. Maturitas, 2000, 36, 165, incorporated herein by reference in its entirety). Similarly, the 5-HT2A receptor antagonist mianserin also had efficacy in treating hot flushes (Takagi S.; Yanagisawa, Y. Sanfujinka No Sekai (World Obstet Gynecol) 1986, 36, 853, incorporated herein by reference in its entirety). It has also been reported that the combination of a norepinephrine reuptake inhibitor with a 5-HT2A receptor antagonist results in enhanced activity in animal models of thermoregulatory dysfunction (Deecher D. C.; Merchenthaler, I. J. WO 2004/035036, incorporated herein by reference in its entirety).
Besides the attention in the scientific community to modulators of the 5-HT receptors, there is also a growing interest in developing new inhibitors of the norepinephrine reuptake. It has been hypothesized that norepinephrine reuptake inhibitors have benefit in the treatment of conditions associated with norepinephrine dysfunction and include, for example, vasomotor symptoms (VMS), major depressive disorder, sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, diabetic neuropathy, nervous system disorders, and stress and urge urinary incontinence, attention deficit disorder, and pain including chronic pain, neuropathic pain and antinociceptive pain. (Zhou, J. Drugs of the Future 2004, 29(12), 1235, incorporated herein by reference in its entirety).
Due to the large number of people afflicted by the disorders related to the 5-HT6 and 5-HT2A receptors and to norepinephrine reuptake, there is a need to develop new compounds, methods, and pharmaceutical compositions to treat and alleviate these conditions. This invention addresses these needs and others.